A shift has begun to take place in both the cancer research community and in funding agencies that support tumor biology as to the relative importance of mutation vs. microenvironmental control in differentiation and cancer. There is increased appreciation of the role of the microenvironment and "context" in both normal tissue function and cancer initiation and progression. Indeed, NCI has initiated an "extraordinary funding opportunity" program to extend its signatures of the cancer cell to its microenvironment. "Scientists pursuing this promising new scientific opportunity will read not only the signatures of cancer cells but also signatures of seemingly normal cells within the tumor microenvironment and signatures that reflect changes that occur as cancer cells interact with the host microenvironment." Tyler Jacks and Bob Weinberg, in a mini review in Cell (Dec.2002) commented on the work from the laboratory of one of the organizers of this meeting and her collaborators, and concluded with the following: "Suddenly the study of cancer cells in two dimensions seems quaint if not archaic"! Thus, thinking of cells as part of a larger structural entity is an area ripe for a sea change. However, the general understanding and appreciation of the complexity and the extent of the microenvironment's influence on tissue function and dysfunction is limited, and at times simplistic. To move the field in this area so that thoughtful and significant research could be accomplished would require an in-depth dialogue between the vast majority of cell and molecular biologists who concentrate on the molecules and those who have worked in the context of the tissue and the host. The goal of this meeting is not only to bring together past and the present research in this field, but also point the way to where we need to go now that we have many of the tools that are necessary to understand this complexity (Radisky and Bissell, 2004). We will bring together a number of experts who have done pioneering work in the role of the microenvironment, and some of the new talents who have joined the field, and showcase recent exciting developments and chart a map for accelerating future exploration and interactions. We need to capture more brilliant minds to enter this area. In this first Keystone meeting on tumor microenvironment, we propose to unravel the excitement and the promise of the field.